Laminopathies are a group of genetic disorders caused by dominant mutations in the human LMNA gene, which encodes the developmentally regulated A-type lamins. Lamins are intermediate filaments that line the inner nuclear membrane and provide structural support for the nucleus. Patients with laminopathies exhibit phenotypes of aging, including cardiac and skeletal muscle dysfunction, dysplasia, diabetes, and premature aging. Lamins are nearly ubiquitously expressed, however many laminopathies exhibit tissue-specific phenotypes, including heart problems. The underlying molecular basis of the cardiac pathology is not well understood. Given that many of the laminopathy patients die from cardiomyopathy, it is vital to understand the functions of lamins in the heart. The majority o mutations in LMNA that cause heart disease result in single amino acid substitutions within the lamin rod and Ig-fold domains. There is a lack of efficient genetic models to functionally dissect the physiological and pathological role(s) of mutant lamins in heart dysfunction. To determine molecular basis of the cardiac pathology associated with mutation of lamin, we have established a novel Drosophila melanogaster model. Using tissue-specific expression tools, mutant lamins are expressed specifically in the heart. Expression of wild-type lamin transgene caused no obvious phenotypes. In contrast, expression of mutant lamin transgene resulted in cardiac dysfunction accompanied by cytoplasmic aggregation and impairment of cellular redox homeostasis. We hypothesize that cytoplasmic lamin aggregation triggers signaling pathways that alter cellular redox homeostasis and results in cardiac dysfunction. To mimic the human disease condition in which mutant lamins are expressed in all tissues, we will use the newly developed CRISPR/Cas9 expression approach. In Specific Aim 1, we will define the progressive cardiac dysfunction at the physiological, functional, biochemical and ultrastructural levels that are caused by mutant lamins. In Specific Aim 2, we will identify genetic and pharmacological suppressors of the cardiac phenotypes caused by mutant lamins. The outcome of proposed study will determine if lamin aggregation and/or reductive stress is a cause of cardiac dysfunction associated with mutant lamins. Candidate suppressors (genetic and/or pharmacological) include factors involved in protein aggregation clearance pathways and redox homeostasis. Our results will identify the molecular basis of cardiac dysfunction in laminopathies and identify potential novel targets for therapy. In future research, we will test our novel routes of therapy on cardiomyocytes generated from iPS cells from laminopathy patients and mouse models of laminopathies.